The ovarian/menstrual cycle is a complex event characterized by an estrogen rich follicular phase and, after ovulation, a progesterone rich luteal phase. Each has duration of approximately 14 days resulting in an intermenstrual interval of about 28 days. The endometrial tissue responds to the changes in hormonal milieu.
The onset of menstruation is the beginning of a new menstrual cycle and is counted as day 1. During a span of about 5 to 7 days, the superficial layers of the endometrium, which grew and developed during the antecedent ovarian/menstrual cycle, are sloughed because demise of the corpus luteum in the non-fertile menstrual cycle is associated with a loss of progesterone secretion. Ovarian follicular maturation occurs progressively resulting in a rise in the circulating levels of estrogen, which in turn leads to new endometrial proliferation.
The dominant ovarian follicle undergoes ovulation at mid-cycle, generally between menstrual cycle days 12 to 16 and is converted from a predominantly estrogen source to a predominantly progesterone source (the corpus luteum). The increasing level of progesterone in the blood converts the proliferative endometrium to a secretory phase in which the tissue proliferation has promptly abated, leading to the formation of endometrial glands or organs. When the ovulated oocyte is viably fertilized and continues its progressive embryonic cleavage, the secretory endometrium and the conceptus can interact to bring about implantation (nidation), beginning about 6 to 8 days after fertilization.
If an ongoing pregnancy is to be established via implantation, the embryo will attach and burrow into the secretory endometrium and begin to produce human chorionic gonadotropin (HCG). The HCG in turn stimulates extended corpus luteum function, i.e. the progesterone production remains elevated, and menses does not occur in the fertile menstrual cycle. Pregnancy is then established. In the non-fertile menstrual cycle, the waning level of progesterone in the blood causes the endometrial tissue to be sloughed. This starts a subsequent menstrual cycle.
Because endometrial proliferation serves to prepare the uterus for an impending pregnancy, manipulation of hormones and of the uterine environment can provide contraception. For example, estrogens are known to decrease follicle stimulating hormone secretion by feedback inhibition.
Progestins can also provide contraception. Endogenous progesterone after estrogen is responsible for the progestational changes of the endometrium and the cyclic changes of cells and tissue in the cervix and the vagina. Administration of progestin makes the cervical mucus thick, tenacious and cellular which is believed to impede spermatozoal transport. Administration of progestin also inhibits luteinizing hormone secretion and blocks ovulation in humans.
Several devices and pharmaceutical compositions are available for the prevention of undesirable conception in the case of regular and planned coitus. For example, condom, pessary, intrauterine devices as well as the different mono- or multi-phasic oral contraceptives. The most prevalent form of oral contraception is a pill that combines an estrogen and/or a progestin, a so-called combined oral contraceptive preparation.
Further sometimes unintentional pregnancies occur for number of reasons. Certainly, they can occur following sexual intercourse when neither party uses a contraceptive device or drug. However, this is by no means, the only reason for unintended pregnancies. Condoms are known to break; diaphragms to slip; and traditional contraceptive pills are, by their own admission, not 100 percent effective, even when taken properly. Its use may also be justified following a rape and noncompliance with the dosing of oral contraceptives. Thus when pills are missed, particularly with the newer, low-dose products, the risk of pregnancy increases substantially. In fact, each year in the U.S. alone, approximately 750,000 pregnancies occur to women using traditional oral contraceptive regimens. Of course, some of these pregnancies occur because the patient has failed to completely and dogmatically follow the prescribed pharmaceutical regimen.
Emergency contraceptive (“EC”) pills are an available treatment for women who are concerned they may have become pregnant by their most recent unprotected sexual encounter. These pills are intended for administration within days, and preferably within hours after unprotected sex and often contain relatively high doses of for example, a progestin and/or an estrogen. Reports in the scientific literature describe other drugs, which may be effective for emergency contraception as well. Dosages and protocols will vary with the drug(s) used. However, in each case, the “pills” help to prevent pregnancy, i.e. either preventing a fertilized ovum from implanting in the lining of the uterus and/or depending on the timing of intercourse, preventing the sperm from fertilizing an egg. Usually one tablet of levonorgestrel 0.75 mg should be taken orally as soon as possible within 72 hours after unprotected intercourse. The second tablet should be taken 12 hours after the first dose. Efficacy is better if levonorgestrel is taken as directed as soon as possible after unprotected intercourse. Further 1.5 mg of levonorgestrel can also be administered at one time as an emergency contraceptive pill. But all such emergency contraceptive pills, which contain high doses of contraceptive hormone, are associated with high incidence of nausea and vomiting. Further if vomiting occurs within three hours of taking the tablet; another tablet of emergency contraceptive pill should be taken immediately.
Norgestrel and levonorgestrel, namely/the D isomer of norgestrel [.+−.-17.{acute over (α)}.-13-ethyl-17-hydroxy-18,19-dinorpregn-4-en-20-in-3-on] have been used in combined preparations as contraceptives for a long time. Further the dose range of levonorgestrel, as emergency contraceptive pill is 1.50 mg in single or divided doses.
Another common problem associated with oral contraceptives as well as an emergency contraceptive pill is the incidence of nausea, which occurs, in a significant percentage of patients. Women may experience vomiting and nausea as major side effect due to contraceptive. It had been observed that about 23.1% of patient experience nausea and 5.6% vomiting when 0.75 mg of levonorgestrel is administered. This is not only uncomfortable, but may also compromise the efficacy of the contraceptive as the associated vomiting may expel out the contraceptive pill. Certainly, a woman who has taken an emergency contraceptive pill and has had an adverse effect, is less likely to take the steps to assure efficacy, including taking more emergency contraceptive pills. The Yuzpe method is among the most common means of emergency contraception. The Yuzpe method requires the use of large quantities of both progestin and estrogen. Thus this method entails numerous side effects of which the most predominant are nausea (54-74%) and vomiting (24-30%) which causes nonobservance of the prescribed treatment by the patient. The concomitant use of a dimenhydrinate salt (100 mg) thirty to sixty minutes prior to the Yuzpe method results in either the prevention or the attenuation of the aforementioned side effects. But it becomes cumbersome for the patient to remember to take dimenhydrinate salt prior to administration of emergency contraceptive, which reduces patient compliance.
Chinese patent CN 1485093 discloses a combination of maxeran preparation and acyeterion.
Canadian patent CA2354250 disclose use of dimenhydrate salt for the prevention or attenuation of adverse side effects associated with the administration of high doses of female hormones along with Yuzpe method. This patent application does not reduce the amount of hormone treatment but just adds dimenhydrinate in its regimen. But the drawback of administration of dimenhydrinate is its sedation properties and it has 4-6 hours of duration.
Therefore, there remains a need for an improved oral contraceptive formulation which shows reduced incidence of nausea and vomiting associated with the administration of oral contraceptive and in turn increases the patient compliance. Further the drowsiness associated with prior art is also mitigated.
Further it has also been recommended in the current therapy that if vomiting occurs within three hours of taking the tablet; another tablet of emergency contraceptive pill should be taken immediately to prevent contraceptive failure. Thus the present invention also eliminates the need to administer second pill to substitute the expelled emergency contraceptive pill. This alleviates patient anxiety related to contraceptive failure and also reduces the chance of administration of another dose of oral contraceptive.